FDA Grants Nivolumab Breakthrough Designation in Renal Cell Carcinoma

Nivolumab (Opdivo) has received an FDA breakthrough therapy designation for the treatment of patients with advanced renal cell carcinoma (RCC), according to Bristol-Myers Squibb (BMS), the manufacturer of the PD-1 inhibitor.

The designation, which will expedite the development and review of nivolumab in RCC, is based on the CheckMate-025 trial. The phase III study was stopped early in July after an independent panel determined that nivolumab improved overall survival (OS) versus everolimus (Afinitor) in patients with advanced RCC. The CheckMate-025 data will be presented at the 2015 European Cancer Congress, according to BMS, which also announced its intent to file for regulatory approval this year.

“Results from CheckMate-025 mark the third tumor in which Opdivo has shown an overall survival benefit in a phase III trial. The breakthrough therapy designation in advanced renal cell carcinoma is a clear signal of the need for additional treatment approaches for RCC and reflects part of our broad commitment to immuno-oncology research that may address many types of advanced cancers,” Michael Giordano, MD, senior vice president, head of development, Oncology, at BMS, said in a statement.

The open-label, parallel assignment CheckMate-025 trial randomized 821 previously treated patients with advanced or metastatic clear-cell RCC to 3 mg/kg of IV nivolumab every 2 weeks or 10 mg of oral everolimus daily until progression or unacceptable toxicity. Prior treatment with one or two antiangiogenic treatment regimens for advanced or metastatic disease was required, along with evidence of disease progression within 6 months of enrollment.

OS was the primary endpoint, with secondary outcome measures including objective response rate (ORR) and progression-free survival (PFS). When the trial was halted after meeting its primary endpoint, eligible patients in the everolimus cohort were allowed to cross over and receive nivolumab in an open-label extension of the study.

Previously published phase II data demonstrated clinical activity for nivolumab with acceptable toxicity in 168 patients with metastatic RCC (mRCC) who had previously received anti-VEGF therapy.1 Seventy percent of patients in the study (n = 118) had received more than one prior systemic regimen.

In a blinded 1:1:1 randomization, patients received either 0.3 (n = 60), 2.0 (n = 54), or 10 mg/kg (n = 54) of IV nivolumab once every 3 weeks. PFS was the primary outcome measure, with secondary endpoints including ORR and OS.

Fatigue was the most frequently reported adverse event (AE), with rates of 24%, 22%, and 35%, in the 0.3-, 2.0-, and 10-mg/kg cohorts, respectively. Grade 3/4 treatment-related AEs were reported for 11% of patients (n = 19) in the overall study population.

Nivolumab is the second drug to recently receive a breakthrough designation from the FDA for the treatment of patients with kidney cancer. In August, breakthrough status was granted to the multikinase inhibitor cabozantinib (Cometriq) as a treatment for patients with advanced RCC following one prior therapy.

Nivolumab was initially approved in December 2014 for patients with unresectable or metastatic melanoma following treatment with ipilimumab (Yervoy) or a BRAF inhibitor. In March 2015, the PD-1 inhibitor was approved for the treatment of patients with advanced squamous non–small cell lung cancer (NSCLC) who have progressed on or after platinum-based chemotherapy.

The FDA is currently reviewing applications for frontline nivolumab as a monotherapy and in combination with ipilimumab for patients with advanced melanoma, as well as an indication for patients with previously treated nonsquamous NSCLC.